1. Field of the Invention
The present invention relates to a system and method for maintaining continuous, long-term control of a concentration of a substance in a patient, and for determining a constant or time-varying profile of the target concentration of said substance. More particularly, the present invention relates to a system and method for maintaining continuous, long-term control of the blood glucose concentrations of a diabetic patient around a target profile using a control algorithm, for example, a feedback or model-based controller, coupled with intradermal (ID) delivery of insulin, which is preferably a short-acting insulin analog delivered via a single-needle or multi-needle array.
2. Description of the Related Art
Intradermal (ID) delivery of insulin has been recently shown to produce more rapid uptake and clearance of therapy than subcutaneous (SC) delivery of insulin, as well as increased bioavailability. This rapid onset reduces the lag time between injection (e.g., infusion commanded by a controller) and patient response.
ID delivery of insulin also avoids complications associated with intravenous (IV) delivery, and therefore, can be effectively employed in a feedback controlled insulin delivery system. A feedback control system operates to adjust a controlled variable (e.g., an insulin delivery rate or volume) based on a comparison of some measurement of a system, such as blood or tissue glucose, to a setpoint. Such a feedback control system may employ calculations encompassing the measured signal and the integral or derivative of that signal, and can thus be limited in performance by time lags associated with the system being controlled. These time lags can be due to, for example, the pharmacokinetics (PK) and pharmacodynamics (PD) of a delivered drug and its targets, any delays inherent in the measuring device, and computation time.
Therefore, it is noted that any decrease in time lags afforded by, for example, ID delivery of insulin, can result in increased performance capability of such a feedback controller. Additionally, any shortening of the therapeutic effect, for example, by way of ID delivery or the use of a short-acting insulin analog, can increase the performance of such a feedback-controlled system. Since an insulin delivery system cannot remove insulin from the patient, except by waiting for the natural PK/PD decay of activity, a shorter therapeutic time will allow for a more flexible and responsive controller.
Furthermore, certain types of patient model structures, that is, certain physiologically based models, may require that the patient undergo an insulin response test, the length of which is determined by the sampling rate and the duration of the insulin response. The use of short acting insulin reduces this time requirement relative to that required for regular insulin. Similarly, use of ID delivery of regular insulin reduces the time requirement relative to SC delivery. However, the use of intradermally delivered short-acting insulin should reduce that time even further, since both the response profile and the possible sampling intervals can be shortened.
In addition, even in non-physiologically based models, such as a 3-compartment minimal model, some insulin sensitivity parameters would preferably be generated for a patient. The duration of any such test can be shortened by use of an insulin delivery route, which provides a fast and short lived response such as that which is provided by ID delivery of short-acting insulin.
Furthermore, any feedback-controlled system for glucose will typically require a sensor to measure and transmit glucose concentrations. This sensor could measure arterial, venous or interstitial fluid concentrations, and might be located on an arm or a leg. There are thus potential inherent delays between arterial glucose and sensed glucose concentrations, which can range up to 30–40 minutes. A control system operating with a shorter sampling interval will be able to tolerate more delays in the sensor. Sensor delays may also be temporary, such as those caused by a momentary interruption in communications, accidental contact with or dislodging of the sensor, and so on. A more frequent interrogation of the sensor will thus allow for a more rapid identification of problems, and a more rapid return to control once problems are overcome.
There have been attempts to implement control of the blood glucose level of a diabetic patient using intravenous (IV) delivery of insulin, or SC delivery of short-acting insulin coupled with relatively long sampling intervals. IV delivery is generally problematic because of the need for an invasive implantation of a pump or delivery device in the patient. In a system that employs relatively non-invasive SC delivery with long sample intervals, control performance is reduced.
It is further noted that the three state model describing plasma glucose concentration as a function of plasma insulin and insulin concentration in a remote compartment currently exists. However, this model overestimates the effect of glucose concentration on cellular glucose uptake, and underestimates the contribution of elevated insulin levels. The result of the mis-match between observed physiological behavior and this three state model would be degraded controller performance.
In addition, the goal of a controller typically is to keep a system parameter (e.g., blood glucose) at or near a target value (e.g., 80 or 100 mg/dl). Because the blood glucose level of uncontrolled diabetics is typically much higher than the desired target level, when a controller is first applied to a new patient, there is a potentially large difference between the current glucose level and the target level. If a controller, such as a model predictive controller (MPC), is instructed to bring a patient's blood glucose from a hyperglycemic value to a typical target value in the shortest possible time, the result will be a rapid input of insulin, which may in turn result in hypoglycemia. If the MPC controller is instructed to keep the patient at the current hyperglycemic state, and then to gradually bring the target glucose down to a typical target value, the result will be a gradual input of insulin, with far less chance of hypoglycemia.
A conventional mode of initiating a controller would be to bring the patient to a glucose level near the target before control is begun. This could be done via manual insulin injection and/or manipulation of glucose intake. However, while technically simple, this approach would be time consuming for the patient and unreliable.
Examples of systems and devices generally related to the above fields of endeavor are described in U.S. Pat. Nos. 6,558,351, 6,441,747, 5,569,186, 5,558,640, 4,494,950 and 4,475,901, in published U.S. Patent Application No. US 2002.0095134 A1 (owned by Becton Dickinson and Company), in published European Patent Application No. EP 1 048 264 A1, in published International Patent Application No. WO 00/74753 A1, in published International Patent Application No. WO 02/02179, and in the following publications: Robert Parker and Francis Doyle, Advances in Drug Delivery Reviews, 48, pp. 211–228 (2001); Parker, R. S., Doyle, F. J., Peppas, N. A. The Intravenous Route to Blood Glucose Control IEEE Engineering in Medicine and Biology, pp. 65–73 (2001); Parker, R. S., Doyle, F. J., Peppas, N. A. A Model-Based Algorithm for Blood Glucose Control in Type I Diabetic Patients IEEE Transactions on Biomedical Engineering, 46(2), pp. 148–157 (1999); “Investigational device mimics a pancreas, brings an artificial pancreas one step closer to reality” ADA Annual Meeting—SAN FRANCISCO—Jun. 17, 2002 (obtained from, www.medtronics,com); The ADICOL (ADvanced Insulin COntrol using a closed Loop) Consortium (www.adicol.org); Biostator algorithm (Clemens, A. H., Feedback Control Dynamics for Glucose Controlled Infusion System Med Prog Technol, 6, pp. 91–98 (1979); Parker, R. S., et al., Robust H-infinity Glucose Control in Diabetes Using a Physiological Model, AIChE J. 46 (12), pp. 2537–2549 (2000); Shimoda, S. et al., Closed-loop subcutaneous insulin infusion algorithm with a short-acting insulin analog for long-term clinical application of a wearable artificial endocrine pancreas, Frontiers Med. Biol. Engng 8 (3): 197–211 (1997); Sorensen, J. T., A Physiologic Model of Glucose Metabolism in Man and its Use to Design and Assess Improved Insulin Therapies for Diabetes, PhD Thesis, M.I.T. (1985); Chassin, L. J. et al., Simulating closed-loop glucose control: Effect of delay in glucose measurement. Diabetes 51: 1606 Suppl. 2. (2002); Chassin, L. J. and Hovorka, R., Closed-loop glucose control with IV glucose sampling and SC insulin infusion: Evaluation by simulation studies, Diabetologia 44: 792 Suppl. 1 (2001); and R. S. Parker, F. J. Doyle III, J. E. Harting, and N. A. Peppas, Model Predictive Control for Infusion Pump Insulin Delivery, Proceedings of the IEEE Engineering in Medicine and Biology 18th Annual International Conference, paper no. 265, Amsterdam, The Netherlands, 1996, the entire contents of each being incorporated herein by reference.
A need therefore exists for a system and method capable of solving these problems and, in particular, for a minimally-invasive ID delivery device that can deliver insulin to a patient while minimizing the occurrence of hypoglycemia, and which can maintain desired blood glucose concentrations in the patient, while also being capable of operating at high sampling rates so that control performance is not degraded.